1. Field of the Invention:
The present invention relates to the use of selective beta-2 adrenergic antagonists for the decrease of intraocular pressure in animals, especially humans, particularly for the treatment of glaucoma.
2. Description of the Prior Art:
Open angle glaucoma is a progressive disorder of increased intraocular pressure (IOP) which results from excess accumulation of aqueous humor, a fluid which is formed by the ciliary processes in the posterior ocular chamber, and which normally leaves the eye through the trabecular meshwork and Schlemm's canal, located in the lateral angle of the anterior chamber.
Considerable evidence suggests that the adrenergic nervous system plays a significant but complex role in the regulation of intraocular pressure. Sympathetic nerve fibers innervate the ciliary process and trabecular meshwork, and both sympathetic stimulation and locally applied beta-adrenergic agonists, such as epinephrine, reduced intraocular pressure. Beta-adrenergic antagonists, such as timolol (which is effective clinically in treating glaucoma) also reduce intraocular pressure. (Zimmerman, T. N. and Boger, W. P. III, Surv. Opthal. 23: 347-362 (May-June, 1979)).
Adrenergic receptors are generally divided into three groups: alpha adrenergic receptors (mediating smooth muscle contraction), beta.sub.1 adrenergic receptors (mediating cardiac acceleration and fatty acid mobilization), and beta.sub.2 adrenergic receptors (mediating smooth muscle relaxation). Biochemical studies prior to this invention have not indicated whether there are beta-adrenergic receptors in the ciliary processes or trabecular meshwork separate from those in the neighboring iris, which also receives adrenergic innervation. Furthermore, in the ciliary processes themselves, it is not certain whether there are beta-receptors in the secretory epithelium distinct from those on ciliary blood vessels. It also remained to be seen prior to this invention whether any beta receptors present would be beta.sub.1 or beta.sub.2. Such studies, which are disclosed in the present patent application, serve to more clearly ascertain the type of agent ideally useful for the treatment of glaucoma.
As mentioned previously, Zimmerman and Boger, supra, have described the use of timolol, a beta adrenergic antagonist, for the reduction of intraocular pressure, as part of a review on the general use of beta-adrenergic blocking agents in the treatment of glaucoma. These authors describe the use of such beta blockers as dichloroisoproterenol (DCI), pronethalol and propranolol. The latter, introduced in 1964, was until recently the only beta blocking agent released for clinical use in the United States, although more than eighteen drugs of this class are in current use overseas. In 1968, practolol was developed as the first beta blocking agent which selectively inhibits cardiac receptors (beta.sub.1). Atenolol, another selective betal blocker, was synthesized in 1973; in the intervening years, other similar molecules with beta.sub.1 selectivity have come to light. Timolol, recently released for topical opthalmic use, is the first beta blocker released for such use in this country. Several side effects have been found for these prior art beta blockers. Topical application of propranolol causes ocular discomfort and stinging thus limiting its use in eyedrops. Practolol, while decreasing intraocular pressure, has received somewhat less attention after recognition that it causes ocular mucocutaneous syndrome. Timolol, a non-selective beta antagonist, is a promising medication for the treatment of glaucoma and appears to be more effective in lowering IOP than any of the other topical agents while being better tolerated (Zimmerman and Boger, supra, at page 358). Yet to be defined, however, is a possible significant loss of efficacy in some patients using this medication for extended periods. Also, because timolol is a non-selective beta antagonist, the authors recommend caution when using timolol in patients with cardiovacular diseases, such as bradycardia, second degree heart block or heart failure, and in patients with asthma.
Colasanti and Trotter (Journal of Investigative Opthalmology and Visual Science, 18:24 (1979)), disclose the use of H35/25, described as a "selective .beta..sub.2 -antagonist" for the decrease of intraocular tension in adult female cats. They demonstrate that H35/25 had about the same maximal reduction as timolol, described as a "mixed .beta..sub.1 - and .beta..sub.2 -antagonist", and somewhat lesser effect than salbutamol, described as a "selective .beta..sub.2 agonist". The classification of adrenoceptor agents as .beta..sub.1 or .beta..sub.2 has, however, recently been further clarified through the extensive work of Minneman and co-workers (Minneman, K. E. et al, Molecular Pharmacology 16:33 (1979); and Journal of Pharmacology and Experimental Therapeutics Vol. 211:502-508 (1979)). These workers demonstrated that, contrary to the definition of H35/25 as a "selective .beta..sub.2 antagonist", this drug shows no specificity for .beta..sub.1 or .beta..sub.2 adrenergic receptors. This observation is consistent with Colasanti's observation that H35/25 and timolol show about the same effects on intraocular pressure, timolol also being a non-specific adrenoceptor antagonist.
In view of the many side effects brought about by the agents currently used for the decrease of intraocular pressure in glaucoma, a need continues to exist for a highly specific family of intraocular pressure-decreasing agents.